Crystalline forms of [R-(R*, R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)

ABSTRACT

Novel crystalline forms of [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt designated Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, and Form XIX are characterized by their X-ray powder diffraction, solid-state NMR, and/or Raman spectroscopy are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as agents for treating hyperlipidemia, hypercholesterolemia, osteoporosis, and Alzheimer&#39;s disease.

FIELD OF THE INVENTION

The present invention relates to novel crystalline forms of atorvastatinwhich is known by the chemical name[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt useful as pharmaceutical agents, to methods fortheir production and isolation, to pharmaceutical compositions whichinclude these compounds and a pharmaceutically acceptable carrier, aswell as methods of using such compositions to treat subjects, includinghuman subjects, suffering from hyperlipidemia, hypercholesterolemia,osteoporosis, and Alzheimer's disease.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, which isincorporated herein by reference, is currently sold as Lipitor® havingthe chemical name[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate and the formula

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoAreductase. As such, atorvastatin calcium is a potent lipid loweringcompound and is thus useful as a hypolipidemic and/orhypocholesterolemic agent.

U.S. Pat. No. 4,681,893, which is incorporated herein by reference,discloses certain trans-6-[2-(3- or4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-onesincluding trans (±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

U.S. Pat. No. 5,273,995, which is herein incorporated by reference,discloses the enantiomer having the R form of the ring-opened acid oftrans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,ie,[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoicacid which is atorvastatin.

U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837;5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792;5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691;5,510,488; 5,998,633; and 6,087,511, which are herein incorporated byreference, disclose various processes and key intermediates forpreparing amorphous atorvastatin. Amorphous atorvastatin has unsuitablefiltration and drying characteristics for large-scale production andmust be protected from heat, light, oxygen, and moisture.

Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat.Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.

International Published Patent Application Number WO 01/36384 allegedlydiscloses a polymorphic form of atorvastatin calcium.

Stable oral formulations of atorvastatin calcium are disclosed in U.S.Pat. Nos. 5,686,104 and 6,126,971.

Atorvastatin is prepared as its calcium salt, ie,[R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1). The calcium salt is desirable since it enablesatorvastatin to be conveniently formulated in, for example, tablets,capsules, lozenges, powders, and the like for oral administration.Additionally, there is a need to produce atorvastatin in a pure andcrystalline form to enable formulations to meet exacting pharmaceuticalrequirements and specifications.

Furthermore, the process by which atorvastatin is produced needs to beone which is amenable to large-scale production. Additionally, it isdesirable that the product should be in a form that is readilyfilterable and easily dried. Finally, it is economically desirable thatthe product be stable for extended periods of time without the need forspecialized storage conditions.

We have now surprisingly and unexpectedly found novel crystalline formsof atorvastatin. Thus, the present invention provides atorvastatin innew crystalline forms designated Forms V, VI, VII, VIII, IX, X, XI, XII,XIII, XIV, XV, XVI, XVII, XVIII, and XIX. The new crystalline forms ofatorvastatin are purer, more stable, or have advantageous manufacturingproperties than the amorphous product.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to crystalline Form Vatorvastatin and hydrates thereof characterized by the following X-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >10% measured on a Shimadzudiffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)^(a) 4.9 (broad) 9 6.0 15 7.0 100 8.0(broad) 20 8.6 57 9.9 22 16.6 42 19.0 27 21.1 35 ^(a)Relative intensityof 4.9 (broad) 2θ is 9.

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form V atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer:

2θ 5.0 6.1 7.5 8.4 (broad) 8.7 (broad) 9.9 16.7 19.0 21.2

Further, the present invention is directed to crystalline Form Vatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance (ssNMR) spectrum whereinchemical shift is expressed in parts per million:

Assignment Chemical Shift C12 or C25 185.7 C12 or C25 176.8 C16 166.9Aromatic Carbons 138.7 C2-C5, C13-C18, 136.3 C19-C24, C27-C32 133.0128.4 122.0 117.0 116.3 C8, C10 68.0 Methylene Carbons 43.1 C6, C7, C9,C11 C33 25.6 C34 19.9

Additionally, the present invention is directed to crystalline Form Vatorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹:

3062 1652 1604 1528 1478 1440 1413 1397 1368 1158 1034 1001 825 245 224130

In a preferred embodiment of the first aspect of the invention,crystalline Form V atorvastatin is a trihydrate.

In a second aspect, the present invention is directed to crystallineForm VI atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)^(a) 7.2 11 8.3 77 11.0 20 12.4 11 13.8 916.8 14 18.5 100 19.7 (broad) 22 20.9 14 25.0 (broad) 15 ^(a)Relativeintensity of 13.8 (broad) 2θ is 9.

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VI atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer:

2θ  7.3  8.5 11.2 12.7 14.0 17.1 (broad) 18.7 19.9 21.1 (broad) 25.2(broad)

Further, the present invention is directed to crystalline Form VIatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Assignment Chemical Shift C12 or C25 176.5 C16 or C12 or C25 168.2 C16or C12 or C25 163.1 C16 or C12 or C25 159.8 Aromatic Carbons 136.8C2-C5, C13-C18, 127.8 C19-C24, C27-C32 122.3 118.8 113.7 C8, C10 88.2C8, C10 79.3 70.5 Methylene Carbons 43.3 C6, C7, C9, C11 36.9 31.9 C33,C34 25.9 C33, C34 22.5

In a third aspect, the present invention is directed to crystalline FormVII atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 8.6 76 10.2 70 12.4 (broad) 12 12.8 (broad)15 17.6 20 18.3 (broad) 43 19.3 100 22.2 (broad) 14 23.4 (broad) 23 23.8(broad) 26 25.5 (broad) 16

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer:

2θ 8.7 10.2 12.4 12.9 17.6 18.4 19.4 22.2 23.5 23.9 25.6

Further, the present invention is directed to crystalline Form VIIatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Assignment Chemical Shift C12 or C25 186.5 C12 or C25 183.3 C12 or C25176.8 C16 166.5 159.2 Aromatic Carbons 137.6 C2-C5, C13-C18, 128.3C19-C24, C27-C32 122.3 119.2 C8, C10 74.5 C8, C10 70.3 C8, C10 68.3 C8,C10 66.2 Methylene Carbons 43.5 C6, C7, C9, C11 40.3 C33, C34 26.3 C33,C34 24.9 C33, C34 20.2

Additionally, the present invention is directed to crystalline Form VIIatorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹:

Raman Spectrum 3060 2927 1649 1603 1524 1476 1412 1397 1368 1159 1034998 824 114

In a preferred embodiment of the third aspect of the invention,crystalline Form VII atorvastatin is a sesquihydrate.

In a fourth aspect, the present invention is directed to crystallineForm VIII atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)^(a)  7.5 61  9.2 29 10.0 16 12.1 10 12.8 613.8 4 15.1 13 16.7 (broad) 64 18.6 (broad) 100 20.3 (broad) 79 21.2 2421.9 30 22.4 19 25.8 33 26.5 20 27.4 (broad) 38 30.5 20 ^(a)Relativeintensity of 12.8 2θ is 6 and 13.8 2θ is 4.

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form VIII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer:

2θ  7.5  9.3 10.1 12.2 12.8 13.8 15.1 16.6-16.9 18.5-18.9 20.2-20.6 21.322.0 22.5 25.9 26.5 27.4 (broad) 30.6

Further, the present invention is directed to crystalline Form VIIIatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Assignment Chemical Shift C12 or C25 186.1 C12 or C25 179.5 C16 167.9C16 161.0 Aromatic Carbons 139.4 C2-C5, C13-C18, 132.9 C19-C24, C27-C32128.7 124.7 121.8 116.6 C8, C10 67.0 Methylene Carbons 43.3 C6, C7, C9,C11 C33, C34 26.7 C33, C34 24.7 C33, C34 20.9 C33, C34 20.1

Additionally, the present invention is directed to crystalline Form VIIIatorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹:

Raman Spectrum 3065 2923 1658 1603 1531 1510 1481 1413 997 121

In a preferred embodiment of the fourth aspect of the invention,crystalline Form VIII atorvastatin is a dihydrate.

In a fifth aspect, the present invention is directed to crystalline FormIX atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)  8.8 50  9.4 (broad) 32 11.2-11.7 (broad)26 16.7 59 17.5 (broad) 33 19.3 (broad) 55 21.4 (broad) 100 22.4 (broad)33 23.2 (broad) 63 29.0 (broad) 15

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form IX atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer:

2θ  9.0  9.4 10.0-10.5 (broad)   11.8-12.0 (broad)   16.9 17.5 (broad)19.4 (broad) 21.6 (broad) 22.6 (broad) 23.2 (broad) 29.4 (broad)

In a sixth aspect, the present invention is directed to crystalline FormX atorvastatin and hydrates thereof characterized by the following X-raypowder diffraction pattern expressed in terms of the 2θ and relativeintensities with a relative intensity of >10% measured on a Shimadzudiffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)  4.7 35  5.2 24  5.8 11  6.9 13  7.9 53 9.2 56  9.5 50 10.3 (broad) 13 11.8 20 16.1 13 16.9 39 19.1 100 19.8 7121.4 49 22.3 (broad) 36 23.7 (broad) 37 24.4 15 28.7 31

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form X atorvastatin expressed in terms of the 2θ values wasmeasured on an Inel (capillary) diffractometer:

2θ  4.7  5.2  5.8  6.9  7.9  9.2  9.6 10.2-10.4 11.9 16.2 16.9 19.1 19.921.5 22.3-22.6 23.7-24.0 (broad) 24.5 28.8

Further, the present invention is directed to crystalline Form Xatorvastatin and hydrates thereof characterized by the followingsolid-state ¹³C nuclear magnetic resonance spectrum wherein chemicalshift is expressed in parts per million:

Assignment Chemical Shift C12 or C25 187.0 C12 or C25 179.5 C16 165.5C16 159.4 Aromatic Carbons 137.9 C2-C5, C13-C18, 134.8 C19-C24, C27-C32129.4 127.9 123.2 119.9 C8, C10 71.1 Methylene Carbons 43.7 C6, C7, C9,C11 40.9 C33 26.4 25.3 C34 20.3 18.3

Additionally, the present invention is directed crystalline Form Xatorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹:

Raman Spectrum 3062 2911 1650 1603 1525 1478 1411 1369 1240 1158 1034999 824 116

In a preferred embodiment of the sixth aspect of the invention,crystalline Form X atorvastatin is a trihydrate.

In a seventh aspect, the present invention is directed to crystallineForm XI atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 10.8 (broad) 58 12.0 12 13.5 11 16.5 5217.6-18.0 (broad) 35 19.7 82 22.3 100 23.2 26 24.4 28 25.8 17 26.5 3027.3 31 28.7 19 29.5 12 30.9 (broad) 17 32.8 (broad) 11 33.6 (broad) 1536.0 (broad) 15 38.5 (broad) 14

In an eighth aspect, the present invention is directed to crystallineForm XII atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)^(a)  5.4 11  7.7 24  8.0 25  8.6 42  8.9 25 9.9 36 10.4 (broad) 24 12.5 18 13.9 (broad) 9 16.2 10 17.8 70 19.4 10020.8 51 21.7 13 22.4-22.6 (broad) 18 24.3 19 25.5 24 26.2 11 27.1 8^(a)Relative intensity of 13.9 (broad) 2θ is 9 and 27.1 2θ is 8.

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer:

2θ  5.4  7.7  8.1  8.6  8.9 10.0 10.5 12.6   14.0 (broad) 16.2 17.9 19.420.9 21.8 22.5-22.8 (broad) 24.4 25.6 26.4 27.2

Additionally, the present invention is directed crystalline Form XIIatorvastatin and hydrates thereof characterized by the following Ramanspectrum having peaks expressed in cm⁻¹:

Raman Spectrum 3064 2973 2926 1652 1603 1527 1470 1410 1367 1240 11591034 1002 823

In a ninth aspect, the present invention is directed to crystalline FormXIII atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aShimadzu diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 8.4 100 8.9 82 15.7 (broad) 45 16.4 (broad)46 17.6 (broad) 57 18.1 (broad) 62 19.7 (broad) 58 20.8 (broad) 91 23.8(broad 57

In a tenth aspect, the present invention is directed to crystalline FormXIV atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 5.4 41 6.7 31 7.7 100 8.1 35 9.0 65 16.5(broad) 15 17.6 (broad) 17 18.0-18.7 (broad) 21 19.5 (broad) 18

In an eleventh aspect, the present invention is directed to crystallineForm XV atorvastatin and hydrates thereof characterized by the followingX-ray powder diffraction pattern expressed in terms of the 2θ andrelative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 5.7 26 6.1 21 6.8 18 7.5 39 8.1 39 8.5 429.5 33 10.5 (broad) 18 19.1-19.6 (broad) 32

In a twelfth aspect, the present invention is directed to crystallineForm XVI atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%) 5.2 37 6.4 34 7.5 100 8.7 79 10.5 (broad)19 12.0 (broad) 10 12.7 (broad) 17 16.7  26 18.3 (broad) 27 19.5  2320.1-20.4 (broad) 37 21.2-21.9 (broad) 32 22.9-23.3 (broad) 38 24.4-25.0(broad) 35

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XVI atorvastatin expressed in terms of the 2θ valueswas measured on a Shimadzu diffractometer with CuK_(α) radiation:

2θ 7.6 8.8 10.2 12.5 16.8 18.2 19.3 20.5 23.0 24.8

In addition, the following X-ray powder diffraction pattern ofcrystalline Form XVI atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer:

2θ 5.1 6.2 7.3 8.7 10.2 (broad) 12.0 (broad) 12.7 (broad) 16.7  18.0(broad) 19.5 (broad) 20.0-20.5 (broad)   21.5-21.6 (broad)   22.9-23.3(broad)   24.0-25.0 (broad)  

In a thirteenth aspect, the present invention is directed to crystalline5 Form XVII atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)  5.0 27  6.1 33  7.3 100  7.9 30  8.5 29 9.1 22 10.0 45 12.1 (broad) 24 14.8 17 16.0-16.5 (broad) 20 17.5(broad) 28 19.0 (broad) 46 19.5 65 20.2 (broad) 47 21.3 64 21.6 55 22.045

In a fourteenth aspect, the present invention is directed to crystallineForm XVIII atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)  8.0 100 9.2 (broad) 52 9.7 (broad) 40 12.124 16.6 (broad)  48 18.5 67

Additionally, the following X-ray powder diffraction pattern ofcrystalline Form XVIII atorvastatin expressed in terms of the 2θ valueswas measured on a Shimadzu diffractometer with CuK_(α) radiation:

2θ 7.7 9.3 9.9 12.2 16.8 18.5

In addition, the following X-ray powder diffraction pattern ofcrystalline Form XVIII atorvastatin expressed in terms of the 2θ valueswas measured on an Inel (capillary) diffractometer:

2θ  7.9  9.2 (broad)  9.8 (broad) 12.2 (broad) 16.7 (broad) 18.5

In a fifteenth aspect, the present invention is directed to crystallineForm XIX atorvastatin and hydrates thereof characterized by thefollowing X-ray powder diffraction pattern expressed in terms of the 2θand relative intensities with a relative intensity of >10% measured on aBruker D5000 diffractometer with CuK_(α) radiation:

Relative Intensity 2θ (>10%)  5.2 32  6.3 28  7.0 100  8.6 74 10.5 3411.6 (broad) 26 12.7 (broad) 35 14.0 15 16.7 (broad) 30 18.9 86 20.8 9423.6 (broad) 38 25.5 (broad) 32

As inhibitors of HMG-CoA reductase, the novel crystalline forms ofatorvastatin are useful hypolipidemic and hypocholesterolemic agents aswell as agents in the treatment of osteoporosis and Alzheimer's disease.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of crystalline Form V,Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, FormXIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, or Form XIXatorvastatin in unit dosage form in the treatment methods mentionedabove. Finally, the present invention is directed to methods forproduction of Form V, Form VI, Form VII, Form VIII, Form IX, Form X,Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII,Form XVIII, or Form XIX atorvastatin.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further described by the following nonlimiting exampleswhich refer to the accompanying FIGS. 1 to 35, short particulars ofwhich are given below.

FIG. 1

Diffractogram of Form V atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 2

Diffractogram of Form VI atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 3

Diffractogram of Form VII atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 4

Diffractogram of Form VIII atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 5

Diffractogram of Form IX atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 6

Diffractogram of Form X atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 7

Diffractogram of Form XI atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 8

Diffractogram of Form XII atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 9

Diffractogram of Form XIII atorvastatin carried out on Shimadzu XRD-6000diffractometer.

FIG. 10

Diffractogram of Form XIV atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 11

Diffractogram of Form XV atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 12

Diffractogram of Form XVI atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 13

Diffractogram of Form XVII atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 14

Diffractogram of Form XVIII atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 15

Diffractogram of Form XIX atorvastatin carried out on Bruker D 5000diffractometer.

FIG. 16

Diffractogram of Form V atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 17

Diffractogram of Form VI atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 18

Diffractogram of Form VII atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 19

Diffractogram of Form VIII atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 20

Diffractogram of Form IX atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 21

Diffractogram of Form X atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 22

Diffractogram of Form XII atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 23

Diffractogram of Form XVI atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 24

Diffractogram of Form XVIII atorvastatin carried out on Inel XRG-3000diffractometer.

FIG. 25

Solid-state ¹³C nuclear magnetic resonance spectrum with spinning sidebands identified by an asterisk of Form V atorvastatin.

FIG. 26

Solid-state ¹³C nuclear magnetic resonance spectrum with spinning sidebands identified by an asterisk of Form VI atorvastatin.

FIG. 27

Solid-state ¹³C nuclear magnetic resonance spectrum with spinning sidebands identified by an asterisk of Form VII atorvastatin.

FIG. 28

Solid-state ¹³C nuclear magnetic resonance spectrum with spinning sidebands identified by an asterisk of Form VIII atorvastatin.

FIG. 29

Solid-state ¹³C nuclear magnetic resonance spectrum of Form Xatorvastatin.

FIG. 30

Raman spectrum of Form V.

FIG. 31

Raman spectrum of Form VI.

FIG. 32

Raman spectrum of Form VII.

FIG. 33

Raman spectrum of Form VIII.

FIG. 34

Raman spectrum of Form X.

FIG. 35

Raman spectrum of Form XII.

DETAILED DESCRIPTION OF THE INVENTION

Crystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X, FormXI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, FormXVIII, and Form XIX atorvastatin may be characterized by their X-raypowder diffraction patterns, by their solid state nuclear magneticresonance spectra (NMR), and/or their Raman spectra.

X-Ray Powder Diffraction Forms V, VI, VII, VIII, IX, X, XI, XII, XIII,XIV. XV, XVI, XVII. XVIII, and XIX

Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII,or XIX atorvastatin were characterized by their X-ray powder diffractionpattern. Thus, the X-ray diffraction patterns of Forms V, VI, VII, VIII,IX, X, XI, XII, or Form XIII atorvastatin were carried out on a ShimadzuXRD-6000 X-ray powder diffractometer using CuK_(α) radiation. Theinstrument is equipped with a fine-focus X-ray tube. The tube voltageand amperage were set at 40 kV and 40 mA, respectively. The divergenceand scattering slits were set at 10, and the receiving slit was set at0.15 mm. Diffracted radiation was detected by a NaI scintillationdetector. A theta-two theta continuous scan at 3°/min (0.4 sec/0.02°step) from 2.5 to 40° 2θ was used. A silicon standard was analyzed eachday to check the instrument alignment. The X-ray diffraction patterns ofForms XIV, XV, XVI, XVII, XVIII, and XIX were carried out on a BrukerD5000 diffractometer using copper radiation, fixed slits (1.0, 1.0, 0.6mm), and a Kevex solid state detector. Data was collected from 3.0 to40.0 degrees in 2θ using a step size of 0.04 degrees and a step time of1.0 seconds. It should be noted that Bruker Instruments purchasedSiemans; thus, a Bruker D 5000 instrument is essentially the same as aSiemans D 5000.

The X-ray diffraction patterns of Forms V, VI, VII, VIII, IX, X, XII,XVI, and XVIII were also carried out on an Inel diffractometer. X-raydiffraction analyses were carried out on an Inel XRG-3000diffractometer, equipped with a Curved Position Sensitive (CPS) detectorwith a 2θ range of 120 degrees. Real time data were collected usingCuK_(α) radiation starting at approximately 4° 2θ at a resolution of0.03° 2θ. The tube voltage and amperage were set to 40 kV and 30 mA,respectively. Samples were prepared for analysis by packing them intothin-walled glass capillaries. Each capillary was mounted onto agoniometer head that is motorized to permit spinning of the capillaryduring data acquisition. Instrument calibration was performed dailyusing a silicon reference standard. The Inel diffractograms for theavailable forms are shown in the figures without baseline subtraction.Calculating the intensities from these diffractograms is within theskill of the art and involves using baseline subtraction to account forbackground scattering (e.g., scattering from the capillary).

To perform an X-ray powder diffraction measurement on a Shimadzu orBruker instrument like the ones used for measurements reported herein,the sample is typically placed into a holder which has a cavity. Thesample powder is pressed by a glass slide or equivalent to ensure arandom surface and proper sample height. The sample holder is thenplaced into the instrument (Shimadzu or Bruker). The source of the X-raybeam is positioned over the sample, initially at a small angle relativeto the plane of the holder, and moved through an arc that continuouslyincreases the angle between the incident beam and the plane of theholder. Measurement differences associated with such X-ray powderanalyses result from a variety of factors including: (a) errors insample preparation (e.g., sample height), (b) instrument errors (e.g.,flat sample errors), (c) calibration errors, (d) operator errors(including those errors present when determining the peak locations),and (e) preferred orientation. Calibration errors and sample heighterrors often result in a shift of all the peaks in the same directionand by the same amount. Small differences in sample height on a flatholder lead to large displacements in XRPD peak positions. A systematicstudy showed that, using a Shimadzu XRD-6000 in the typicalBragg-Brentano configuration, sample height differences of 1 mm led topeak shifts as high as 1° 2θ (Chen, et al., J. Pharmaceutical andBiomedical Analysis, 2001; 26:63). These shifts can be identified fromthe X-ray diffractogram and can be eliminated by compensating for theshift (applying a systematic correction factor to all peak positionvalues) or recalibrating the instrument. In contrast, the Inelinstrument used herein places the sample in a capillary which ispositioned at the center of the instrument. This minimizes sample heighterrors (a) and preferred orientation (e). Since, when using capillaries,the sample height is not established manually, the peak locations fromthe Inel measurements are typically more accurate than those from theShimadzu or the Bruker instrument. As mentioned above, it is possible torectify measurements from the various machines by applying a systematiccorrection factor to bring the peak positions into agreement. Ingeneral, this correction factor will bring the peak positions from theShimadzu and Bruker into agreement with the Inel and will be in therange of 0 to 0.2° 2θ.

Table 1 lists the 2θ and relative intensities of all lines in the samplewith a relative intensity of >10% for crystalline Forms V-XIXatorvastatin. The numbers listed in this table are rounded numbers.

TABLE 1 Intensities and Peak Locations of All Diffraction Lines WithRelative Intensity Greater Than 10%^(a) for Forms V to XIX (Measured onShimadzu Diffractometer) Form V Form VI Form VII Form VIII Form IX FormX Form XI Form XII Rela- Rela- Rela- Rela- Rela- Rela- Rela- Rela- tivetive tive tive tive tive tive tive Inten- Inten- Inten- Inten- Inten-Inten- Inten- Inten- sity sity sity sity sity sity sity sity 2θ (>10%)2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%)4.9* 9 7.2 11 8.6 76 7.5 61 8.8 50 4.7 35 10.8* 58 5.4 11 6.0 15 8.3 7710.2 70 9.2 29 9.4* 32 5.2 24 12.0 12 7.7 24 7.0 100 11.0 20 12.4* 1210.0 16 11.2-11.7* 26 5.8 11 13.5 11 8.0 25 8.0* 20 12.4 11 12.8* 1512.1 10 16.7 59 6.9 13 16.5 52 8.6 42 8.6 57 13.8 9 17.6 20 12.8 6 17.5*33 7.9 53 17.6-18.0* 35 8.9 25 9.9 22 16.8 14 18.3* 43 13.8 4 19.3* 559.2 56 19.7 82 9.9 36 16.6 42 18.5 100 19.3 100 15.1 13 21.4* 100 9.5 5022.3 100 10.4* 24 19.0 27 19.7* 22 22.2* 14 16.7* 64 22.4* 33 10.3* 1323.2 26 12.5 18 21.1 35 20.9 14 23.4* 23 18.6* 100 23.2* 63 11.8 20 24.428 13.9* 9 25.0* 15 23.8* 26 20.3* 79 29.0* 15 16.1 13 25.8 17 16.2 1025.5* 16 21.2 24 16.9 39 26.5 30 17.8 70 21.9 30 22.4 19 19.1 100 27.331 25.8 33 19.8 71 28.7 19 19.4 100 26.5 20 21.4 49 29.5 12 20.8 5127.4* 38 22.3* 36 30.9* 17 21.7 13 30.5 20 23.7* 37 32.8* 11 22.4-22.6*18 24.4 15 33.6* 15 24.3 19 28.7 31 36.0* 15 25.5 24 38.5* 14 26.2 1127.1 8 Form XIII Form XIV Form XV Form XVI Form XVII Form XVIII Form XIXRela- Rela- Rela- Rela- Rela- Rela- Rela- tive tive tive tive tive tivetive Inten- Inten- Inten- Inten- Inten- Inten- Inten- sity sity sitysity sity sity sity 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ (>10%) 2θ(>10%) 2θ (>10%) 8.4 100 5.4 41 5.7 26 5.2 37 5.0 27 8.0 100 5.2 32 8.982 6.7 31 6.1 21 6.4 34 6.1 33 9.2* 52 6.3 28 15.7* 45 7.7 100 6.8 187.5 100 7.3 100 9.7* 40 7.0 100 16.4* 46 8.1 35 7.5 39 8.7 79 7.9 3012.1 24 8.6 74 17.6* 57 9.0 65 8.1 39 10.5* 19 8.5 29 16.6* 48 10.5 3418.1* 62 16.5* 15 8.5 42 12.0* 10 9.1 22 18.5 67 11.6* 26 19.7* 58 17.6*17 9.5 33 12.7* 17 10.0 45 12.7* 35 20.8* 91 18.0-18.7* 21 10.5* 18 16.726 12.1* 24 14.0 15 23.8* 57 19.5* 18 19.1-19.6* 32 18.3* 27 14.8 1716.7* 30 19.5 23 16.0-16.5* 20 18.9 86 20.1-20.4* 37 17.5* 28 20.8 9421.2-21.9* 32 19.0* 46 23.6* 38 22.9-23.3* 38 19.5 65 25.5* 3224.4-25.0* 35 20.2* 47 21.3 64 21.6 55 22.0 45 *Broad Forms XIV, XV,XVI, XVII, XVIII, and XIX were measured on Brucker D-5000Diffractometer. ^(a)Relative intensity for Form V 4.9 (broad) 2θ is 9;Form VI 13.8 2θ is 9; Form VIII 12.8 2θ is 6 and 13.8 2θ is 4; and FormXII 13.9 (broad) 2θ is 9 and 27.1 2θ is 8.

Because only 19 crystalline forms of atorvastatin are known, each formcan be identified and distinguished from the other crystalline forms byeither a combination of lines or a pattern that is different from theX-ray powder diffraction of the other forms.

For example, Table 2 lists combination of 2θ peaks for Forms V to XIXatorvastatin, i.e., a set of X-ray diffraction lines that are unique toeach form. Forms I to IV atorvastatin disclosed in U.S. Pat. Nos.5,969,156 and 6,121,461 are included for comparison.

TABLE 2 Forms I to XIX Unique Combination of 2θ Peaks Form I Form IIForm III Form IV Form V Form VI Form VII Form VIII Form IX Form X 9.08.5 8.3 4.7 6.0 7.2 8.6 7.5 8.8 4.7 9.3 9.0 16.4 5.2 7.0 8.3 10.2 9.29.4* 6.9 10.1 17.1-17.4 19.9 7.7 8.0* 11.0 12.8* 10.0 16.7 7.9 10.4 20.524.2 9.4 9.9 18.5 17.6 16.7* 17.5* 9.2 11.7 10.1 16.6 18.3* 18.6* 19.3*9.5 12.0 19.3 20.3* 21.4* 19.1 16.8 29.0* 19.8 30.0 Form XI Form XIIForm XIII Form XIV Form XV Form XVI Form XVII Form XVIII Form XIX 10.8*7.7 8.4 5.4 5.7 5.2 6.1 8.0 5.5 16.5 8.0 8.9 6.7 6.1 6.4 7.3 9.2* 7.019.7 8.6 20.8* 7.7 7.5 7.5 7.9 16.6* 8.6 22.3 8.9 23.8* 8.1 8.1 8.7 10.018.5 10.5 9.9 9.0 8.5 16.7 19.0* 12.7* 17.8 9.5 20.1-20.4* 19.5 18.919.4 19.1-19.6* 22.9-23.3* 21.3 20.8 21.6 *Broad Forms I to XIII weremeasured on Shimadzu XRD-6000 diffractometer. Forms XIV to XIX weremeasured on Bruker D 50001 diffractometer. Form II 2θ peaks from U.S.Pat. No. 5,969,156.

Solid State Nuclear Magnetic Resonance (NMR) Methodology

Solid-state ¹³C NMR spectra were obtained at 270 or 360 MHz Tecmaginstruments. High-power proton decoupling and cross-polarization withmagic-angle spinning at approximately 4.7 and 4.2 kHz or 4.6 and 4.0 kHzwere used for 68 MHz (¹³C frequency) data acquisition, 4.9 and 4.4 kHzwere used for 91 MHz (¹³C frequency) data acquisition. The magic anglewas adjusted using the Br signal of KBr by detecting the side bands. Asample was packed into a 7 mm Doty rotor and used for each experiment.The chemical shifts were referenced externally to adamantine except forForm X where the chemical shifts are arbitrary.

Table 3 shows the solid-state NMR spectrum for crystalline Forms V, VI,VII, VIII, and X atorvastatin.

TABLE 3

Chemical Shifts for Forms V, VI, VII, VIII, and X Atorvastatin ChemicalShift V VI VII VIII X 185.7 186.5 186.1 187.0 183.3 179.5 176.8 176.5176.8 179.5 166.9 168.2 166.5 167.9 165.5 163.1 161.0 159.8 159.2 159.4138.7 136.8 137.6 139.4 137.9 136.3 132.9 134.8 133.0 129.4 128.4 127.8128.3 128.7 127.9 124.7 123.2 122.0 122.3 122.3 121.8 118.8 119.2 119.9117.0 116.3 116.6 113.7 88.2 74.5 79.3 70.5 70.3 71.1 68.0 68.3 67.066.2 43.1 43.3 43.5 43.3 43.7 40.3 36.9 40.9 31.9 25.6 25.9 26.3 26.726.4 24.9 24.7 25.3 22.5 20.2 20.9 20.3 19.9 20.1 18.3 Forms V, VI, VII,VIII, and X: Relative peak intensity over 20 are shown here (4.5, 4.6,4.7, or 4.9 kHz CPMAS). Spectra were obtained using two differentmagic-angle spinning rates to determine spinning sidebands. Form X:Relative peak intensity over 20 are shown here (5.0 kHz CPMAS).

Table 4 shows unique solid-state NMR peaks for Forms V, VI, VII, VIIIand X atorvastatin, ie, peaks within ±1.0 ppm. Forms I to IVatorvastatin are included for comparison.

TABLE 4 Forms I to VIII and X Unique Solid-State NMR Peaks Form I FormII Form III Form IV Form V Form VI Form VII Form VIII Form X 182.8 181.0161.0 181.4 176.8 163.1 183.3 132.9 18.3 131.1 163.0 140.1 63.5 36.9176.8 73.1 161.0 131.8 17.9 31.9 74.5 64.9 140.5 69.8 35.4

Raman Spectroscopy Methodology

The Raman spectrum was obtained on a Raman accessory interfaced to aNicolet Magna 860 Fourier transform infrared spectrometer. The accessoryutilizes an excitation wavelength of 1064 nm and approximately 0.45 W ofneodymium-doped yttrium aluminum garnet (Nd:YAG) laser power. Thespectrum represents 64 or 128 co-added scans acquired at 4 cm⁻¹resolution. The sample was prepared for analysis by placing a portioninto a 5-mm diameter glass tube and positioning this tube in thespectrometer. The spectrometer was calibrated (wavelength) with sulfurand cyclohexane at the time of use.

Table 5 shows the Raman spectra for Forms V, VI, VII, VIII, X, and XIIatorvastatin.

TABLE 5 Raman Peak Listing for Forms V, VI, VII, VIII, X and XIIAtorvastatin Form V Form VI Form VII Form VIII Form X Form XII 3062 30583060 3065 3062 3064 2973 2935 2927 2923 2911 2926 1652 1651 1649 16581650 1652 1604 1603 1603 1603 1603 1603 1528 1556 1524 1531 1525 15271525 1510 1481 1478 1478 1476 1478 1470 1440 1413 1412 1412 1413 14111410 1397 1397 1368 1368 1369 1367 1240 1240 1158 1157 1159 1158 11591034 1034 1034 1034 1001 997 998 997 999 1002 825 824 824 823 245 224130 114 121 116 Relative peak intensity over 20 are shown.

Table 6 lists unique Raman peaks for Forms V, VI, VII, VIII, X, and XIIatorvastatin, ie, only one other form has a peak with ±4 cm⁻¹. In thecase of Forms VI and X, it is a unique combination of peaks. Forms I toIV atorvastatin are included for comparison.

TABLE 6 Forms I to VIII, X and XII Unique Raman Peaks Form I Form IIForm III Form IV Form V Form VI* Form VII Form VIII Form X* Form XII3080 1663 2938 423 1440 3058 1397 1510 3062 2973 1512 359 1660 215 13972935 1481 2911 1439 1510 132 130 1556 1413 1525 142 1481 1525 121 12401427 1182 859 *Unique combination of Raman peaks

Crystalline Forms V to XIX atorvastatin of the present invention mayexist in anhydrous forms as well as hydrated and solvated forms. Ingeneral, the hydrated forms are equivalent to unhydrated forms and areintended to be encompassed within the scope of the present invention.Crystalline Form XIV contains about 6 mol of water. Preferably, Form XIVcontains 6 mol of water. Crystalline Forms V, X, and XV atorvastatincontain about 3 mol of water. Preferably, Forms V, X, and XVatorvastatin contain 3 mol of water.

Crystalline Form VII contains about 1.5 mol of water. Preferably, FormVII atorvastatin contains 1.5 mol of water. Crystalline Form VIIIcontains about 2 mol of water. Preferably, Form VIII atorvastatincontains 2 mol of water.

Crystalline Forms XVI-XIX may exist as a solvate.

Crystalline forms of atorvastatin of the present invention, regardlessof the extent of hydration and/or salvation having equivalent x-raypowder diffractograms, ssNMR, or Raman spectra are within the scope ofthe present invention.

Crystalline forms, in general, can have advantageous properties. Apolymorph, solvate, or hydrate is defined by its crystal structure andproperties. The crystal structure can be obtained from X-ray data orapproximated from other data. The properties are determined by testing.The chemical formula and chemical structure does not describe or suggestthe crystal structure of any particular polymorphic or crystallinehydrate form. One cannot ascertain any particular crystalline form fromthe chemical formula, nor does the chemical formula tell one how toidentify any particular crystalline solid form or describe itsproperties. Whereas a chemical compound can exist in three states-solid,solution, and gas-crystalline solid forms exist only in the solid state.Once a chemical compound is dissolved or melted, the crystalline solidform is destroyed and no longer exists (Wells J. I., Aulton M. E.Pharmaceutics. The ‘Science of Dosage Form Design. Reformulation, AultonM. E. ed., Churchill Livingstone, 1988; 13:237).

The new crystalline forms of atorvastatin described herein haveadvantageous properties. Form VII has good chemical stability, which iscomparable to Form I (disclosed in U.S. Pat. No. 5,969,156). Sincenoncrystalline forms of atorvastatin are not chemically stable, this isa significant advantage, which would translate into enhanced shelf lifeand longer expiration dating. Form VII can be prepared fromacetone/water, whereas Form I is prepared from the more toxicmethanol/water system. Form VII is the sesquihydrate and contains lesswater, meaning that a unit weight of Form VII contains more atorvastatinmolecules, meaning it is of higher potency.

The ability of a material to form good tablets at commercial scaledepends upon a variety of drug physical properties, such as theTableting Indices described in Hiestand H. and Smith D., Indices ofTableting Performance, Powder Technology, 1984; 38:145-159. Theseindices may be used to identify forms of atorvastatin calcium which havesuperior tableting performance. One such index is the Brittle FractureIndex (BFI), which reflects brittleness, and ranges from 0 (good—lowbrittleness) to 1 (poor—high brittleness). For example, Form VII has aBFI value 0.09, while Form I has a BFI value 0.81. Thus, Form VII isless brittle than Form I. This lower brittleness indicates greater easeof manufacture of tablets.+

Form VIII also has less water than Form I (dihydrate vs trihydrate) andthus a gram of Form VIII contains more atorvastatin molecules.

Form X is advantageous in that it can be prepared from the less toxicisopropanol (IPA):water system, thus avoiding the more toxicmethanol:water system.

Form XII has the highest melting point (210.6). Since high melting pointcorrelates with stability at high temperature, this means this form ismost stable at temperatures near the melting point. High melting formscan be advantageous when process methods involving high temperatures areused. Form XII is also prepared from the less toxic tetrahydrofuran(THF) water system.

Form XIV is prepared using the less toxic THF/water system.

The present invention provides a process for the preparation ofcrystalline Forms V to XIX atorvastatin which comprises crystallizingatorvastatin from a solution in solvents under conditions which yieldcrystalline Forms V to XIX atorvastatin.

The precise conditions under which crystalline Forms V to XIXatorvastatin are formed may be empirically determined, and it is onlypossible to give a number of methods which have been found to besuitable in practice.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either compounds or a corresponding pharmaceuticallyacceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from two or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.5 mg to 100 mg, preferably 2.5 mg to 80 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as hypolipidemic and/or hypocholesterolemic agentsand agents to treat osteoporosis and Alzheimer's disease, thecrystalline Forms V to XIX atorvastatin utilized in the pharmaceuticalmethod of this invention are administered at the initial dosage of about2.5 mg to about 80 mg daily. A daily dose range of about 2.5 mg to about2θ mg is preferred. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1[R—(R*,R*)]-2-(4-Fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid hemi calcium salt (Forms V-XIX Atorvastatin) Form V AtorvastatinMethod A

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was slurried ina mixture of acetonitrile/water (9:1) to afford crystalline Form Vatorvastatin.

Method B

Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) wasslurried in a mixture of acetonitrile/water (9:1) at 60° C. overnight,filtered, and air dried to afford crystalline Form V atorvastatin.

Method C

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was stressedunder vapors of acetonitrile/water (9:1) to afford crystalline Form Vatorvastatin.

Method D

Acetonitrile was added to a solution of amorphous atorvastatin calcium(U.S. Pat. No. 5,273,995) in tetrahydrofuran/water (9:1) and cooled toafford crystalline Form V atorvastatin.

Method E

Acetonitrile was added to a solution of amorphous atorvastatin calcium(U.S. Pat. No. 5,273,995) in dimethylformamide/water and fastevaporation affords crystalline Form V atorvastatin.

Method F

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) diffused in avapor of acetonitrile/water (9:1) to afford crystalline Form Vatorvastatin.

Crystalline Form V atorvastatin, mp 171.40° C., trihydrate Karl Fischer4.88% (3 mol of water).

Form VI Atorvastatin Method A

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) was placed intoa vapor jar containing dimethylformamide/water (9:1) for 20 days toafford crystalline Form VI atorvastatin.

Method B

Fast evaporation of a dimethylformamide/water solution of amorphousatorvastatin calcium (U.S. Pat. No. 5,273,995) afforded crystalline FormVI atorvastatin.

Method C

Fast evaporation of a dimethylformamide/water (saturated) solution ofamorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) seeded withcrystalline Form VI afforded crystalline Form VI atorvastatin.Crystalline Form VI atorvastatin, mp 145.9° C.

Form VII Atorvastatin Method A

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetone/water (1:1) (5.8 mg/mL) was stirred overnight. A solid formedwhich was filtered to afford crystalline Form VII atorvastatin.

Method B

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetone/water (1:1) was evaporated at 50° C. to afford crystallineForm VII atorvastatin.

Method C

A saturated solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in acetone/water (1:1) was seeded with crystalline Form VIIatorvastatin to afford crystalline Form VII atorvastatin.

Method D

Fast evaporation of a saturated solution of amorphous atorvastatincalcium (U.S. Pat. No. 5,273,995) in acetone/water (1:1) was seeded withcrystalline Form VII to afford crystalline Form VII atorvastatin.Crystalline Form VII atorvastatin, mp 195.9° C., 1.5 hydrate KarlFischer 2.34% (1.5 mol of water).

Form VIII Atorvastatin Method A

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in dimethylformamide/water (saturated) (9:1), was seeded withcrystalline Form VII and evaporated to afford crystalline Form VIIIatorvastatin.

Method B

Fast evaporation of a solution of amorphous atorvastatin calcium (U.S.Pat. No. 5,273,995) in dimethylformamide/water (9:1) affords crystallineForm VIII atorvastatin.

Crystalline Form VIII atorvastatin, mp 151° C., dihydrate Karl Fischer2.98% (2 mol of water).

Form IX Atorvastatin Method A

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetone/water (6:4) (3.4 mg/mL) was evaporated on a rotary evaporatorto afford crystalline Form IX atorvastatin.

Method B

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetone/water (6:4) was filtered, seeded with crystalline Form IXevaporated on a rotary evaporator to afford crystalline Form IXatorvastatin.

Method C

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetone/water (6:4) was stirred for 0.5 hours, filtered, evaporatedon rotary evaporator to concentrate the solution, and dried in a vacuumoven to afford crystalline Form IX atorvastatin.

Form X Atorvastatin Method A

A slurry of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) inisopropanol/water (9:1) was stirred for a few days, filtered, and airdried to afford crystalline Form X atorvastatin.

Method B

A slurry of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995) inisopropanol/water (9:1) was stirred for 5 days, filtered, and air driedto afford crystalline Form X atorvastatin.

Method C

A saturated solution of amorphous atorvastatin calcium (U.S. Pat. No.5,273,995) in isopropanol/water (9:1) was stirred for 2 days, filtered,and air dried to afford crystalline Form X atorvastatin. CrystallineForm X atorvastatin, mp 180.1° C., trihydrate Karl Fischer 5.5% (3.5 molof water).

Form XI Atorvastatin

A solution of amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995)in acetonitrile/water (9:1) was filtered and allowed to evaporate slowlyto afford crystalline Form XI atorvastatin.

Form XII Atorvastatin

Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) wasslurried in tetrahydrofuran/water (2:8) at 90° C. for 5 days, filtered,and air dried to afford crystalline Form XII atorvastatin.

Crystalline Form XII atorvastatin, mp 210.6° C.

Form XIII Atorvastatin

Crystalline Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) wasadded to 10 mL 2:8 water:methanol to leave a layer of solid on thebottom of a vial. The slurry was heated to about 70° C. for 5 days. Thesupernatant was removed, and the solid air dried to afford crystallineForm XIII atorvastatin.

Form XIV Atorvastatin

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g, wasslurried for 3 weeks in 45 mL of isopropyl alcohol/5 mL of water (9:1)at ambient temperature. The mixture was filtered to afford crystallineForm XIV atorvastatin after drying at ambient temperature.

Differential scanning calorimetry (DSC) indicates a low desolvationevent at about 60° C. (peak) followed by a melt at about 150° C.Combustion analysis indicates that the compound is a hexahydrate.Thermographic infrared spectroscopy (TG-1R) shows the compound containswater. Karl Fischer shows the compound contains 5.8% water.

Form XV Atorvastatin

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g, wasslurried for 3 weeks in 45 mL acetonitrile/5 mL of water (9:1) atambient temperature. The mixture was filtered to afford crystalline FormXV atorvastatin after drying at ambient temperature. DSC indicates a lowdesolvation event at about 78° C. (peak) followed by a melt at about165° C. Combustion analysis indicates that the compound is a trihydrate.TG-1R shows the compound contains water.

Form XVI Atorvastatin

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 1 g, wasslurried for about 1 day in 9:1 acetonitrile/water at room temperature.The mixture was filtered to afford crystalline Form XVI atorvastatinafter drying at ambient temperature. DSC indicates a broad endotherm atpeak temperature of 72° C. and an endotherm with onset temperature of164° C. The weight loss profile by thermographic analysis (TGA)indicates a total weight loss of about 7% at 30° C. to 160° C.Combustion analysis indicates that TGA and Karl Fischer analysis (shows7.1% water) indicates the compound is a tetrahydrate/acetonitrilesolvate.

Form XVII Atorvastatin

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 0.5 g, wasslurried for about 2 days in 5 mL of 9:1 dimethylformamide (DMF)/watercontaining 25 mL of acetonitrile at room temperature. The mixture wasfiltered to afford crystalline Form XVII atorvastatin after drying atambient temperature. DSC showed multiple broad endotherms indicating thecompound was a solvate.

Form XVIII Atorvastatin

Crystalline Form XVI atorvastatin, 0.5 g, was dried for about 1 day atroom temperature to afford crystalline Form XVIII atorvastatin. DSCshowed a broad endotherm at low temperature indicating the compound wasa solvate. Karl Fischer analysis showed the compound contained 4.4%water.

Form XIX Atorvastatin

Amorphous atorvastatin calcium (U.S. Pat. No. 5,273,995), 0.4 g, wasslurried for about 7 days in 4 mL methyl ethyl ketone at roomtemperature. The mixture was filtered to afford crystalline Form XIXatorvastatin after drying at ambient temperature. DSC indicated a lowdesolvation event at about 50° C. (peak) followed by a melt at about125° C. TGA analysis indicates that the compound is a solvate thatdesolvates at low temperature.

1-15. (canceled) 16-18. (canceled)
 19. A method of treatinghyperlipidemia, hypercholesterolemia, osteoporosis or Alzheimer'sDisease comprising administering to a host suffering therefrom atherapeutically effective amount of crystalline Form X or a hydratethereof having an X-ray powder diffraction containing the following 2θvalues measured using CuK_(α) radiation: 4.7, 5.2, 5.8, 6.9, 7.9, 9.2,9.5, 10.3 (broad), 11.8, 16.1, 16.9, 19.1, 19.8, 21.4, 22.3 (broad),23.7 (broad), 24.4, and 28.7, in solid unit dosage form.
 20. A method oftreating hyperlipidemia, hypercholesterolemia, osteoporosis orAlzheimer's Disease comprising administering to a host sufferingtherefrom a therapeutically effective amount of crystalline Form X or ahydrate thereof characterized by solid state ¹³C nuclear magneticresonance having the following chemical shifts expressed in parts permillion: 18.3, 20.3, 25.3, 26.4, 40.9, 43.7, 71.1, 119.9, 123.2, 127.9,129.4, 134.8, 137.9, 159.4, 165.5, 179.5, and 187.0, in solid unitdosage form.
 21. A method of treating hyperlipidemia,hypercholesterolemia, osteoporosis or Alzheimer's Disease comprisingadministering to a host suffering therefrom a therapeutically effectiveamount of crystalline Form X or a hydrate thereof characterized by Ramanspectroscopy having the following peaks expressed in cm⁻¹: 116, 284,999, 1034, 1158, 1240, 1369, 1411, 1478, 1525, 1603, 1650, 2911, and3062, in solid unit dosage form.